Chemists have a new tool that could make it safer to synthesize fluorinated pharmaceuticals, agrochemicals, and materials. The transformation is a riff on the Appel reaction, which turns alcohols into alkyl halides but until now had been incapable of making alkyl fluorides. The reaction uses potassium fluoride (KF) as the fluorine source, sidestepping harsh fluorinating reagents made from hydrogen fluoride (HF), a dangerous chemical (Science 2026, DOI: 10.1126/science.aec6298).
“HF is really the apex fluorochemical out of which all fluorochemicals are derived,” says University of Oxford chemistry professor Véronique Gouverneur, who led the research effort. She’s dedicated her research to instead making calcium fluoride (CaF2) or waste-derived KF central fluorinating agents.
“I’m trying to simplify the entire fluorochemical industry and to simplify the supply chain so that it’s energetically less demanding, so that it’s simplified for everybody involved, and so that it’s much safer,” Gouverneur says. To that end, her team has previously created fluorinating reagents directly from fluorspar and other mineral forms of CaF2.
For this latest work, Gouverneur decided to revisit a reaction that has been used for over 50 years, but where fluorination hasn’t been viable: the Appel reaction.
The Appel reaction uses triphenyl phosphine and a halogen source to turn alcohols into alkyl halides. But, Gouverneur says, “If you put a soluble source of fluoride under Appel-type conditions, you form the difluorophosphorane, and that’s basically a dead end” because the P–F bond is so strong.
This variation of the Appel reaction converts alcohols into alkyl fluorides.
Gouverneur’s team reinvented the reaction by developing a new phosphorus reagent—a bench-stable neopentoxyphosphonium salt designed by postdoctoral researcher Anirban Mondal. When used with KF and a urea-based phase-transfer catalyst, the neopentoxyphosphonium salt forms a pentavalent neopentoxyfluorophosphorane, which then exchanges the neopentoxy group for the alcohol substrate followed by C–F bond formation.
The researchers used the new reaction to transform more than 80 alcohols into their corresponding alkyl fluorides. What’s more, through their choice of urea catalyst, the chemists were able to convert racemic alcohols into enantioenriched alkyl fluorides through a chiral ion–pairing strategy.
Allan J. B. Watson, an organic chemist at the University of St. Andrews who was not involved in the work, says in an email that “despite their utility, the installation of C–F bonds using simple, inexpensive fluoride salts remains a considerable challenge.”
Watson says that the Gouverneur’s latest work “is an important and valuable addition to the fluorination toolbox. The team overcomes two key challenges in a single and, crucially, simple approach, simultaneously providing a useful reaction and a creative solution to a long-standing gap in synthetic methodology.”
The reaction does have limitations. For example, it doesn’t work well with tertiary alcohols unless there’s neighboring group participation. But Gouverneur plans to address that in future work. She says, “I want the simplest possible, most beautiful, and elegant solution to a complex problem.”
